This program-project grant has two interdependent themes: to use molecular biology and genetics both to elucidate the life cycles of human tumor viruses and to characterize the mechanisms by which these tumor viruses transform infected cells. Dr. Lambert studies papillomaviruses; Dr. Loeb studies hepatitis B viruses; Dr. Ahlquist studies papillomavirus and hepadnavirus in collaboration with Drs. Lambert and Loeb; and Drs. Compton and Sugden study human herpesviruses. These investigators use parallel approaches to study most known human tumor viruses. Their shared intellectual and experimental commitments support advances in one family of tumor viruses being applied to another. Dr. Lambert is defining the mechanisms by which human papilloma viral oncogenes affect host cell physiology and support the viral life cycle. He is also dissecting the regulation and replication of papillomaviral plasmids in parallel with Dr. Sugden's research on the replication of Epstein-Barr viral plasmids. Dr. Loeb is elucidating the multiple steps in nucleic acid replication of human hepatitis B virus. Dr. Ahlquist is collaborating with Drs. Lambert and Loeb to adapt yeast for the study of papilloma and hepadnaviral replication to allow genetic identification of host contributions to these human tumor viruses. Dr. Compton is identifying host cell signaling pathways that regulate the life cycle of Kaposi's sarcoma virus. Dr. Sugden is characterizing newly identified features of Epstein-Barr virus required for its maintenance in infected cells. Drs. Sugden and Compton are collaborating to examine similar features in Kaposi's sarcoma virus. All of this research has as its goal understanding carcinogenesis by human tumor viruses which now are responsible for 15%-20% of all human cancers. All of this research uses current robust techniques and is developing new approaches to make the understanding of human tumor viruses possible. All of this research has as its ultimate goal the defining of practical viral targets for the development of rational antiviral therapies for virus-associated human cancers.